1. Field of the Invention
The invention relates to a novel process for preparing substituted indoles of the general formula: ##STR1## which comprises the reaction of a phenylhydrazine acid addition salt of the formula; ##STR2## where X is Cl or Br; R.sub.1 is a member selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl and methoxy; R.sub.2 is a member selected from the group consisting of hydrogen, alkyl having from one to three carbon atoms, --C.sub.6 H.sub.4 R.sub.1, --CH.sub.2 CH.sub.2 NR.sub.7 R.sub.8, and --CH.sub.2 CH.sub.2 CH.sub.2 NR.sub.7 R.sub.8 wherein R.sub.7 and R.sub.8 are each alkyl having from one to three carbon atoms; with the proviso that when R.sub.2 is --C.sub.6 H.sub.4 R.sub.1, both R.sub.1 are the same; with a ketone of the formula ##STR3## wherein R.sub.3 is methyl; R.sub.4 is hydrogen; and R.sub.3 and R.sub.4 when taken together with the ##STR4## moiety to which they are attached form: wherein n is an integer from 3 to 6, or ##STR5## WHEREIN M IS 1 OR 2; R.sub.5 is --COOR.sub.6 or --SO.sub.2 R.sub.6 and R.sub.6 is methyl or ethyl.
Said substituted indoles are old and the prior art teaches their use as pharmaceuticals, pharmaceutical intermediates and for industrial applications as inhibitors in acid pickling of steel and in dry working photographic compositions. U.S. Pat. Nos. 2,541,211; 3,282,942; 3,329,571; 3,925,409, German Pat. No. 930,988 and Belgian Pat. No. 827,451 teach their use as pharmaceuticals and intermediates therefore. U.S. Pat. Nos. 3,329,619; 3,493,376 and Netherlands Pat. No. 6,508,274 teach their use for the above-mentioned industrial applications.
Numbering of tricyclic ring systems discussed herein are as follows: ##STR6##
2. Description of the Prior Art
Numerous reports and reviews concerning the preparation of indole derivatives by the general procedure known as the Fischer indole synthesis have appeared over the past 90 years; see for example, the reviews of Robinson, Chem. Rev., 63, 373 (1963) and ibid., 69, 227 (1969), and Brown, in Heterocyclic Compounds, Wiley Interscience Division of John Wiley and Sons, New York, N.Y., 1972, Vol. 25, Part I, W. J. Houlihan, Editor, pp. 246-316, and references cited therein.
Generally, the Fischer indole synthesis is carried out by heating an arylhydrazone in the presence of an appropriate mineral acid, organic acid or Lewis acid. The arylhydrazone undergoes rearrangement followed by cyclization with elimination of ammonia. The arylhydrazone is ordinarily obtained when the appropriate arylhydrazine and carbonyl compound are heated in a suitable organic solvent. e.g. ethanol or acetic acid.
The broad synthetic applicability of the Fischer indole synthesis depends to a large extent upon the selection, often by trial and error, of a suitable acid catalyst which will permit formation of the indole without decomposition of intermediates or the desired product. However, in those cases where the products or intermediates have poor acid stability, the acid catalyzed reaction fails or affords only low yields. Thermal indolization of arylhydrazones has been proposed as a method for preparation of acid sensitive indoles; see e.g., Brown, loc. cit., p. 259; Kelly et. al., Can. Jour. Chem., 43, 296 (1965) and Crooks et. al., Chem. and Ind., 547 (1967). The thermal indole reaction is carried out by heating arylhydrazones in a high boiling solvent such as ethylene glycol, diethylene glycol or tetralin in the absence of acidic catalysts. This method, which has found only limited use, requires prior isolation of a purified arylhydrazone and is carried out at the boiling point of one of the above mentioned solvents, i.e., 198.degree. to 245.degree. C.
The substituted indoles prepared by the process of the invention are known in the art and their utility in pharmaceutical and industrial applications has been previously disclosed. In each of the following references to utility, the substituted indoles disclosed therein are prepared by the above mentioned Fischer indole synthesis by heating an arylhydrazone in an acid medium:
German Pat. No. 930,988; Chem. Abstr. 52, 17288g (1958) teaches the preparation of indoles and tetrahydrocarbazoles, substituted on the benzene ring by methyl or chloro groups and optionally alkylated on the nitrogen atom. It also discloses their chemotherapeutic action against protozoa, especially Trypanosoma cruzi and their ability to increase the effect of soporifics.
Methods for preparing and using 2-methyl-indole and 2,5-dimethylindole as inhibitors of metal loss and hydrogen absorption in acid pickling of steel are disclosed in U.S. Pat. No. 3,329,619. The utility of 2,5-dimethylindole and 1,2-dimethylindole in dry working photographic compositions is taught in U.S. Pat. No. 3,493,376, and in Netherlands Pat. No. 6,508,274; Chem. Abstr. 64, 18787b (1966), respectively.
U.S. Pat. No. 2,541,211 teaches the preparation of compounds of the formula RAB where R is 1,2,3,4-tetrahydro-5-carbazolyl, A is an alkylene radical containing 2 to 5 carbon atoms and B is a dialkylamino group such as --N(CH.sub.3).sub.2 or --N(C.sub.2 H.sub.5).sub.2 as well as their use as intermediates for the preparation of antihistamines and antispasmodics.
Indole derivatives of the general formula: ##STR7## wherein R.sup.1 is hydrogen, methyl, fluoro, chloro, nitro and methoxy; R.sup.2 is a dialkylaminoalkyl group containing from 4 to 9 carbon atoms and p is an integer from 5 to 13 are disclosed by Rice et. al., Jour. Med. Chem., 7, 313 (1964); U.S. Pat. Nos. 3,282,942 and 3,329,571. They are useful as tranquilizing agents, central nervous system stimulants, appetite depressants and ataractics.
Compounds of the formula: ##STR8## wherein R.sup.3 is selected from the group consisting of fluoro, chloro, bromo, methyl and hydrogen; R.sup.4 is selected from the group consisting of phenyl and phenyl substituted in the 4-position by fluoro, methoxy, and chloro; and R.sup.5 is carbethoxy are intermediates for the preparation of tranquilizing agents. In U.S. Pat. No. 3,925,409 the preparation and use of the compounds in which q is one are disclosed. Preparation and use of the corresponding compounds in which q is two are disclosed in Belgian Pat. No. 827,451 (Derwent No. 68968 W/42).